KR20080048553A - Modifying leukocyte function - Google Patents

Abstract

Use of PREPS and/or L-particles for the manufacture of a medicament for modifying or regulating leukocyte function.

Description

Leukocyte function correction {MODIFYING LEUKOCYTE FUNCTION}

The present invention relates to altering leukocyte function, such as lymphocyte function, in particular, but not exclusively, cytotoxic T lymphocyte (CTL) function.

Cytotoxic T lymphocytes (CTLs) play a vital role in the control of various human diseases, including a wide range of acute and chronic viral infections, such as herpes simplex virus infection. CTLs also play a role in cancer surveillance, that is, to prevent the spread of cancer in patients already afflicted, and also to prevent the spreading of sporadic cancer cells into tumor masses. However, CTL can also cause life-threatening illnesses such as transplant rejection, graft-vs host disease and autoimmunity. Therefore, CTLs do not prevent disease but play an important role in the manifestation of many diseases.

Clearly, the ability to specifically change CTL function will be beneficial for the treatment of various conditions.

CTLs are an important component of many successful immune responses, but they have the potential to harm the host. Therefore, their activity is tightly regulated by multiple receptor-ligand interactions. Before they can act as effectors, CTLs must be activated by Antigen Presenting Cells (APCs) and triggered by target cells. Once activated, the immune system has a mechanism for controlling the CTL response and prevents destruction of healthy host cells. Alternatively, activated CTLs may be deficient in immunity, functionally worsen, unresponsive, or divided into memory-like states.

One object of the present invention is to provide a means for modulating or modifying CTL activity.

A first aspect of the invention provides a method of treating a disease exemplified by the activity or dysfunction of leukocyte (eg, CTL) function, which method exposes leukocytes to one or two PREPS and / or L-particles. Thereby regulating or modifying leukocyte function.

A second aspect of the invention provides a method of modifying or regulating leukocyte function, which method comprises exposing leukocytes (eg, CTL) to one or two PREPS and / or L-particles.

A third aspect of the invention uses PREPS and / or L-particles for the manufacture of a medicament that modifies or modulates the function of white blood cells (eg, CTL).

A fourth aspect of the invention uses PREPS and / or L-particles for the manufacture of a medicament for a condition or condition treatment exemplified by the activity or dysfunction of leukocyte (eg CTL) function.

The bottle or condition is one or more:

Graft versus host disease

Acute organ rejetion

Hashimotos thyroiditis

Primary Myxoedema

Thyrotoxicosis

Pernicious anaemea

Addisions disease

Insulin dependant diabetes mellitus

Goodpastures syndrome

Pemphigus vularis

Pemphigiod

Sympathetic ophthalmia

Autoimmune haemolytic anaemia

Primary thrombocytopenic purpura

Primary leukopenia (Idiopathic leucopenia)

Primary biliary cirrhosis

Active chronic hepatitis

Ulcerative colitis

Sjogrens Syndrome

Rheumatiod Arthritis

Dermatomyositis

Scleroderma

Discoid lupus

Systemic lupus erythematosus.

PREPS and / or L-particles can be used as immunotherapy and / or vaccine.

Additives and / or carriers may be included. Adjuvants can be included in any medicament, such as, for example, metal salts, MPL and RC-529 (both supplied by Corixia Corporation). The medicament may be configured for local, local or systemic injection.

US patent 5384122 discloses non-infected particles called L-particles produced by herpesvirus-infected cells. L-particles consist of an envelope surrounded by an envelope, but are consequently non-contagious because they lack viral capsids and DNA.

US 5384122 (the entire specification is incorporated herein) discloses that L-particles can be used as active components as vaccines for use in the treatment of herpesviruses. In addition, using recombinant herpesviruses comprising DNA encoding foreign proteins or peptides, L-particles can be prepared to contain heterologous proteins or peptides, such that L-particles are associated with herpesvirus infection. Used to fight other infectious diseases.

US Patent 5994116 (currently assigned) discloses an additional type of herpesvirus particles called PREPS (pre-viral DNA replication enveloped particles). PREPS are free of viral capsids and DNA and they include reduced amounts of any protein relative to L-particles and increased amounts of other proteins relative to L-particles.

US 5994116 (the entire specification is incorporated herein) discloses that PREPS can be used as an active component of a vaccine for use in the treatment of a vaccine. In addition, recombinant techniques can be used to generate PREPS having heterologous proteins or peptides incorporated therein, which discloses that PREPS is used to fight herpesviruses and other infectious diseases.

Since CTLs are involved in controlling the incubation period of the acute, soluble phase, and long incubation period of simple herpesvirus (HSV) infection, HSV evolves a number of mechanisms to avoid CTL as part of its survival power.

A study by Sloan et al. (J. Immunol. (2003) 171 pp 6733-6741) demonstrated that HSV-infected fibroblasts send signals to CTL that do not infect CTLs or that contain functionally inhibiting CTLs without cell death. did. These workers are about this process as interactions. Inactive signals significantly reduce the cytotoxicity and cytokine effector function of CTLs, and the inactivated phenotype can persist after CTLs are removed from HSV-infected cells and treated with IL-2.

Inactivation of CTLs can occur due to the effects of PREPS particles on L-particles and CTL functions, and it is believed that using these features leads to the use of PREPS particles and L-particles as immunotherapeutic tools for the treatment of diseases of CTL function. Is suggested.

PREPS and L-particles can be done according to the patents identified above.

Specific uses of α-herpesvirus-derived particles as treatment for CTL-adjusted disease include:

Preventing Acute Rejection of Corneal Grafts

It has been known over 15 years that the risk of rejection of human corneal grafts is greatest given the high consideration of leukocytes in the transplant bed (Ophthalmol. 1989 96 (1) pp 38-44). Since the rejection of the cornea is controlled by the CTL, application of L-particles or PREPS particles to either the corneal bed or the newly implanted cornea by either a local application or an instant injection or delivery device will lead to inactivation of such CTL. This will reduce the risk of acute organ rejection.

Preventing Acute Rejection of Kidney Transplantation

Years of studies of kidney transplantation in non-human primates (accepting incompletely matched transplants) show that graft survival can be increased by disrupting immune function just before surgery. This study is inherent in the innate immune system being ready to negate the induction of allograft resistance, so efficient physiological signal blocking of allogeneic immunity should already be adequately already possible for the development of a tolerogenic environment. (Transpl. Immunol. 2003 11 (3-4): pp 335-44).

Therefore, local injection at the site of the lymph node (eg inguinal node if intraperitoneal transplantation is planned) or at any suitable site prior to surgery (eg, a few days) to reduce the risk of direct graft rejection. Or administration of PREPS or L-particles by systemic injection (intravenously or subcutaneously).

Acute Rheumatism  Joint Injection Affected by Arthritis

Rheumatoid arthritis is a condition characterized by several inflamed joints that are structurally altered by the disease and become painful dysfunction.

Recent studies (Clin. Exp. Rheumatol. 2005; 23 (2): pp 185-92) suggest that joints with high CTL involvement can lead to disease progression with loss of general structure. Application of PREPS or L-particles by direct intraarticular injection leads to disruption of the CTL response, leading to a decrease in inflammatory and tissue disruptive responses.

Excessive activity or dysfunction CTL Prevention of systemic diseases caused by

This includes a number of conditions labeled as "derived tissue disorders" including dermatomyositis, scleroderma, SLE and the like and acute or chronic viral infections such as type C infections and type B infections. Delivery of PREPS or L-particles to the hematopoietic system (bone marrow / liver / spleen / thymus) is a useful method in the modulation of CTL function.

Specific immune modulation PREPS  Or L- Particle  develop

Therefore, while the invention described above relates to L-particles or PREPS composed entirely of herpes virus elements, the broad range of protection is the resulting heterologous protein or epitopic peptide from unrelated viruses or other types of herpes viruses or other microorganisms. (epitopic peptides) and L-particle or PREPS) may be provided by generating a recombinant herpes virus expressing the inserted heterologous DNA. (The term "heterologous" herein means not unique to the strain of the herpes virus from which L-particles or PREPS originate.)

If the heterologous DNA detects only that the heterologous DNA originates from another strain or type of HSV, then the recombinant HSV containing the migrating DNA will express it in most cases without difficulty, so that the resulting protein is contained in L-particles or PREPS (e.g., It is expected to be integrated into the envelope, in the envelope or in the envelope. Recombinant viruses representing mobile proteins insert a gene for that protein located under the control of a suitable HSV signal in the genome of either wild type HSV-1 virus or DNA-replacement negative HSV-1 using standard techniques. (Rixon and McLauchlan, 1993, In: Molecular Virology, A Practical Approach, p. 285-307; ed. Davison AJ and Elliott, RMIRL Press, Oxford). Wild-type viruses carrying heterologous genes can be used with DNA-replicating interference (see above) or can be further designed so that it is DNA-replicating negative. PREPS or L-particles comprising heterologous proteins may also be treated with cells designed to express heterologous genes, along with wild type HSV or DNA-replicating negative HSV-1 in the presence of DNA replication interferers, and by returning appropriate herpes virus signals. Can be generated.

Cytotoxic T lymphocytes (CTLs) can refer to proteins for intercellular pathogens or tumors. Protective antiviral immunity, modulated by the activity of antigen epitope-specific CTLs, can be achieved by delivering an external antigen into the cytosol of antigen-expressing cells. However, cytosolic introduction of vaccine antigens requires specialized delivery strategies due to cell walls that restrict the access of micromolecules to cytosol; L-particles and PREPS provide this technique. The importance of using this technique is that certain T cell responses may be affected by the delivery of non-viral proteins or antigens to T cells, which may prevent specific down regulation of T cell responses by the use of appropriate proteins / antigens. It will modify the immune function of the cell in response to such an antigen or antigens comprising.

While the above description deals with modification of CTL function, within the scope of the present invention, the use of PREPS and / or L-particles to modify the function of other lymphocytes, in fact, preferably all or at least some white blood cells of the animal blood system. do.

Claims (10)

Use of PREPS and / or L-particles for the manufacture of a medicament for modifying or regulating leukocyte function. The method of claim 1, Use of PREPS and / or L-particles characterized by modifying or regulating T lymphocyte function, eg, CTL function. Use of PREPS and / or L-particles for the manufacture of a medicament for the treatment of a condition exemplified by the activity or dysfunction of CTL function. The method of claim 3, wherein The condition is: Graft-versus-host disease Acute organ rejection Hashimoto thyroiditis Primary myxedema Thyroid poisoning Pernicious anemia Addison's disease Insulin-dependent diabetes Good pass syndrome Saengseong Chunpochang Yucheon Pochang Sympathetic Ophthalmitis Autoimmune hemolytic anemia Primary thrombocytopenic purpura Primary leukopenia Primary biliary cirrhosis Active Chronic Sensitivity Ulcerative colitis Sjogren's syndrome Rheumatoid arthritis Dermatitis Scleroderma Discoid lupus Use of PREPS and / or L-particles selected from systemic lupus erythematosus. The method according to any one of claims 1 to 4, Use of PREPS and / or L-particles, wherein the medicament is in the form of an immunotherapy or vaccine. The method according to any one of claims 1 to 5, Use of PREPS and / or L-particles, characterized in that the medicament comprises one or more additives, carriers and / or adjuvant. The method according to any one of claims 1 to 6, Use of PREPS and / or L-particles, wherein the medicament is configured for local, local or systemic administration. In the method of treating a disease exemplified by activation or dysfunction of leukocyte function, A method of treating a disease exemplified by activation or dysfunction of leukocyte function, comprising modulating or modifying leukocyte function by exposing leukocytes to one or both of PREPS and / or L-particles. The method of claim 8, The bottle is: Graft-versus-host disease Acute organ rejection Hashimoto thyroiditis Primary myxedema Thyroid poisoning Pernicious anemia Addison's disease Insulin-dependent diabetes Good pass syndrome Saengseong Chunpochang Yucheon Pochang Sympathetic Ophthalmitis Autoimmune hemolytic anemia Primary thrombocytopenic purpura Primary leukopenia Primary biliary cirrhosis Active Chronic Sensitivity Ulcerative colitis Sjogren's syndrome Rheumatoid arthritis Dermatitis Scleroderma Discoid lupus A method for treating a disease exemplified by activation or dysfunction of leukocyte function, characterized in that it is selected from systemic lupus erythematosus. In a method of modifying or regulating leukocyte function, A method of modifying or modulating leukocyte function, comprising exposing leukocytes to one or both of PREPS and / or L-particles.